Maternal Immune Activation Model Research Articles

Prefrontal Cortex Response to Prenatal Insult and Postnatal Opioid Exposure.

The influence of proinflammatory challenges, such as maternal immune activation (MIA) or postnatal exposure to drugs of abuse, on brain molecular pathways has been reported. On the other hand, the simultaneous effects of MIA and drugs of abuse have been less studied and sometimes offered inconsistent results. The effects of morphine exposure on a pig model of viral-elicited MIA were characterized in the prefrontal cortex of males and females using RNA-sequencing and gene network analysis. Interacting and main effects of morphine, MIA, and sex were detected in approximately 2000 genes (false discovery rate-adjusted p-value < 0.05). Among the enriched molecular categories (false discovery rate-adjusted p-value < 0.05 and −1.5 > normalized enrichment score > 1.5) were the cell adhesion molecule pathways associated with inflammation and neuronal development and the long-term depression pathway associated with synaptic strength. Gene networks that integrate gene connectivity and expression profiles displayed the impact of morphine-by-MIA interaction effects on the pathways. The cell adhesion molecules and long-term depression networks presented an antagonistic effect between morphine and MIA. The differential expression between the double-challenged group and the baseline saline-treated Controls was less extreme than the individual challenges. The previous findings advance the knowledge about the effects of prenatal MIA and postnatal morphine exposure on the prefrontal cortex pathways.

Deficit of perineuronal net induced by maternal immune activation mediates the cognitive impairment in offspring during adolescence

Maternal immune activation (MIA) during pregnancy is considered a risk factor for neurodevelopment in the offspring, resulting in behavioral abnormalities. Furthermore, adolescence is a vulnerable period for developing different psycho-cognitive deficits. Here, we aimed to observe the cognitive consequences of prenatal MIA exposure in adolescents and explored the underlying mechanisms. We divided dams into CON and MIA groups after inducing a mouse model of MIA using lipopolysaccharide (120 μg/kg) on gestational day 15. Open field (OF), elevated plus maze (EPM), and novel object recognition (NOR) tests were performed on postnatal day (PD) 35–37. The expression of hippocampal Wisteria floribunda agglutinin (WFA)+ perineuronal net (PNN), parvalbumin (PV), glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule-1(Iba-1) were evaluated using immunofluorescence, and the expression of matrix metalloprotein-9 (MMP-9) in the hippocampus was assessed using the western blot. Following the infusion of chondroitinase ABC (ChABC) into CA1 in the offspring from the CON group on PD 30, they were divided into ChABC and Sham groups. OF, EPM, and NOR were performed on PD 35–37. Compared to the CON group, decreased exploration time of the novel object and preference ratio were observed in the MIA group. Meanwhile, the MIA group presented significantly decreased WFA+ PNN in CA1, increased Iba-1+ microglia, and MMP-9 in the hippocampus. Additionally, the density of PV+ neurons and GFAP+ astrocytes was comparable between both groups. After digesting the PNN, the exploration time of novel object and preference ratio decreased in the ChABC group compared to the Sham group. Conclusively, the PNN deficit in CA1 caused by prenatal MIA might, at least partially, induce cognitive impairment in adolescents. Microglia and MMP-9 may also be potential candidates for PNN deficit after MIA.

Late prenatal immune activation in mice induces transgenerational effects via the maternal and paternal lineages.

Prenatal exposure to infectious or noninfectious immune activation is an environmental risk factor for neurodevelopmental disorders and mental illnesses. Recent research using animal models suggests that maternal immune activation (MIA) during early to middle stages of pregnancy can induce transgenerational effects on brain and behavior, likely via inducing stable epigenetic modifications across generations. Using a mouse model of viral-like MIA, which is based on gestational treatment with poly(I:C), the present study explored whether transgenerational effects can also emerge when MIA occurs in late pregnancy. Our findings demonstrate that the direct descendants born to poly(I:C)-treated mothers display deficits in temporal order memory, which are similarly present in second- and third-generation offspring. These transgenerational effects were mediated via both the maternal and paternal lineages and were accompanied by transient changes in maternal care. In addition to the cognitive effects, late prenatal immune activation induced generation-spanning effects on the prefrontal expression of gamma-aminobutyric acid (GABA)ergic genes, including parvalbumin and distinct alpha-subunits of the GABAA receptor. Together, our results suggest that MIA in late pregnancy has the potential to affect cognitive functions and prefrontal gene expression patterns in multiple generations, highlighting its role in shaping disease risk across generations.

JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, characterized by marked genetic heterogeneity. In this study, two independent microarray datasets of cerebellum of ASD were integrative analyzed by NetworkAnalyst to screen candidate crucial genes. NetworkAnalyst identified two up-regulated genes, Jun proto-oncogene (JUN) and platelet derived growth factor receptor alpha (PDGFRA), as the most crucial genes in cerebellum of ASD patients. Based on KEGG pathway database, genes associated with JUN in the cerebellum highlight the pathways of Th17 cell differentiation and Th1 and Th2 cell differentiation. Genes associated with PDGFRA in the cerebellum were found enriched in pathways in EGFR tyrosine kinase inhibitor resistance and Rap1 signaling pathway. Analyzing all differentially expressed genes (DEGs) from the two datasets, Gene Set Enrichment Analysis (GSEA) brought out IL17 signaling pathway, which is related to the expression of JUN and PDGFRA. The ImmuCellAI found the elevated expression of JUN and PDGFRA correlating with increased Th17 and monocytes suggests JUN and PDGFRA may regulate Th17 cell activation and monocytes infiltrating. Mice model of maternal immune activation demonstrated that JUN and PDGFRA are up-regulated and related to the ASD-like behaviors that provide insights into the molecular mechanisms underlying the altered IL17 signaling pathway in ASD and may enable novel therapeutic strategies.

Prenatal Zinc Supplementation Ameliorates Hippocampal Astrocytes Activation and Inflammatory Cytokines Expression Induced by Lipopolysaccharide in a Rat Model of Maternal Immune Activation.

Evidence suggests that gestational exposure to Lipopolysaccharide (LPS) results in fetal zinc deficiency and eventually neurodevelopmental abnormalities. In this study, we utilized a rat model of Maternal Immune Activation (MIA) to investigate the possible neuroprotective effects of zinc supplementation during pregnancy on hippocampal astrocytes activation as well as inflammatory cytokines expression in adult offspring. Pregnant rats received intraperitoneal injections of either LPS (0.5 mg/kg) or saline on Gestational Days (GD) 15 and 16, and orally gavaged with zinc sulfate (30 mg/kg) during pregnancy. Astrocyte density and histological assessment were evaluated in the hippocampus of adult offspring on Postnatal Days (PND) 60 to 62. Also, the mRNA levels of IL-6, TNF-α, IL-1β, NF-κB, and GFAP were measured using qPCR analysis. Prenatal exposure to LPS resulted in upregulated expression levels of IL-6, TNF-α, NF-κB, and GFAP in the hippocampus of adult pups. Moreover, the offspring from the LPS group showed an increased astrocyte density in the CA1 region with no histological alterations in CA1 and CA3 areas. However, maternal zinc supplementation ameliorated the LPS-induced inflammatory alterations. This study supports the premise that zinc supplementation during pregnancy might be an early treatment option to inhibit hippocampal inflammation induced by the maternal immune response to infectious agents. Maternal immune activation induced mild hippocampal inflammation in adult offspring.Zinc supplementation suppressed LPS-induced hippocampal inflammation in offspring.Zinc might be an early therapeutic option to inhibit neurodevelopmental impairments. Schizophrenia is a chronic and disabling psychiatric disorder, affecting an estimated one percent of the world's population. To date, the biological mechanisms underlying this mental disorder remain largely elusive, however, research has demonstrated the involvement of both genetic and environmental factors. Of environmental factors, gestational exposure to rubella, influenza, and genital-reproductive infections have gained particular interest among researchers. Based on this evidence, in the present study, we used an animal model of schizophrenia and showed the beneficial effect of zinc supplementation during pregnancy to protect against LPS-induced inflammation in the hippocampus of adult offspring. Collectively, our study provides support for the premise that early treatment might be a suitable option to prevent schizophrenia risk in progeny.

Relationship of Striatal Presynaptic Dopamine to Midbrain Neuromelanin in a Nonhuman Primate Model of Maternal Immune Activation

Maternal infection during pregnancy is a significant risk factor for future mental disorders in offspring. This phenomenon is studied translationally using maternal immune activation (MIA) models. Dopamine (DA) dysregulation is a feature of some MIA model systems. We previously reported increased striatal DA synthesis capacity in a pilot MIA NHP cohort. In the present study, we report data on the relationship between [18F] fluoro-l-m-tyrosine (FMT) PET measures in the striatum and substantia nigra (SN) neuromelanin (NM; a putative noninvasive proxy DA measure) levels in MIA NHP’s.

Using complex behavior to understand brain mechanisms in health and disease.

Using complex behavior to understand brain mechanisms in health and disease.

Virus-Induced Maternal Immune Activation as an Environmental Factor in the Etiology of Autism and Schizophrenia.

Maternal immune activation (MIA) is mediated by activation of inflammatory pathways resulting in increased levels of cytokines and chemokines that cross the placental and blood-brain barriers altering fetal neural development. Maternal viral infection is one of the most well-known causes for immune activation in pregnant women. MIA and immune abnormalities are key players in the etiology of developmental conditions such as autism, schizophrenia, ADHD, and depression. Experimental evidence implicating MIA in with different effects in the offspring is complex. For decades, scientists have relied on either MIA models or human epidemiological data or a combination of both. MIA models are generated using infection/pathogenic agents to induce an immunological reaction in rodents and monitor the effects. Human epidemiological studies investigate a link between maternal infection and/or high levels of cytokines in pregnant mothers and the likelihood of developing conditions. In this review, we discuss the importance of understanding the relationship between virus-mediated MIA and neurodevelopmental conditions, focusing on autism and schizophrenia. We further discuss the different methods of studying MIA and their limitations and focus on the different factors contributing to MIA heterogeneity.

Aberrant Phase Precession of Lateral Septal Cells in a Maternal Immune Activation Model of Schizophrenia Risk May Disrupt the Integration of Location with Reward.

Spatial memory and reward processing are known to be disrupted in schizophrenia. Since the lateral septum (LS) may play an important role in the integration of location and reward, we examined the effect of maternal immune activation (MIA), a known schizophrenia risk factor, on spatial representation in the rat LS. In support of a previous study, we found that spatial location is represented as a phase code in the rostral LS of adult male rats, so that LS cell spiking shifts systematically against the phase of the hippocampal, theta-frequency, local field potential as an animal moves along a track toward a reward (phase precession). Whereas shallow precession slopes were observed in control group cells, they were steeper in the MIA animals, such that firing frequently precessed across several theta cycles as the animal moved along the length of the apparatus, with subsequent ambiguity in the phase representation of location. Furthermore, an analysis of the phase trajectories of the control group cells revealed that the population tended to converge toward a common firing phase as the animal approached the reward location. This suggested that phase coding in these cells might signal both reward location and the distance to reward. By comparison, the degree of phase convergence in the MIA-group cells was weak, and the region of peak convergence was distal to the reward location. These findings suggest that a schizophrenia risk factor disrupts the phase-based encoding of location-reward relationships in the LS, potentially smearing reward representations across space.SIGNIFICANCE STATEMENT It is unclear how spatial or contextual information generated by hippocampal cells is converted to a code that can be used to signal reward location in regions, such as the VTA. Here we provide evidence that the firing phase of cells in the lateral septum, a region that links the two areas, may code reward location in the firing phase of cells. This phase coding is disrupted in a maternal immune activation model of schizophrenia risk such that representations of reward may be smeared across space in maternal immune activation animals. This could potentially underlie erroneous reward processing and misattribution of salience in schizophrenia.

The instrumental role of operant paradigms in translational psychiatric research: Insights from a maternal immune activation model of schizophrenia risk.

Rigorous behavioral analysis is essential to the translation of research conducted using animal models of neuropsychiatric disease. Here we discuss the use of operant paradigms within our lab as a powerful approach for exploring the biobehavioral bases of disease in the maternal immune activation rat model of schizophrenia. We have investigated a range of disease features in schizophrenia including abnormal perception of time, cognition, learning, motivation, and internal state (psychosis), providing complex insights into brain and behavior. Beyond simple phenotyping, implementing sophisticated operant procedures has been effective in delineating aspects of pathological behavior, identifying interacting pathologies, and isolating contributing mechanisms of disease. We provide comment on the strengths of operant techniques to support high‐quality behavioral investigations in fundamental neuropsychiatric research.

Transgenerational Sex-dependent Disruption of Dopamine Function Induced by Maternal Immune Activation.

Several epidemiological studies suggest an association between maternal infections during pregnancy and the emergence of neurodevelopmental disorders in the offspring, such as autism and schizophrenia. Animal models broadened the knowledge about the pathophysiological mechanisms that develop from prenatal infection to the onset of psychopathological phenotype. Mounting evidence supports the hypothesis that detrimental effects of maternal immune activation might be transmitted across generations. Here, we explored the transgenerational effects on the dopamine system of a maternal immune activation model based on the viral mimetic polyriboinosinic-polyribocytidilic acid. We assessed dopamine neurons activity in the ventral tegmental area by in vivo electrophysiology. Furthermore, we studied two behavioral tests strictly modulated by the mesolimbic dopamine system, i.e., the open field in response to amphetamine and the prepulse inhibition of the startle reflex in response to the D2 agonist apomorphine. Second-generation adult male rats did not display any deficit in sensorimotor gating; however, they displayed an altered activity of ventral tegmental area dopamine neurons, indexed by a reduced spontaneous firing rate and a heightened motor activation in response to amphetamine administration in the open field. On the other hand, second-generation female rats were protected from ancestors’ polyriboinosinic-polyribocytidilic acid treatment, as they did not show any alteration in dopamine cell activity or in behavioral tests. These results confirm that maternal immune activation negatively influences, in a sex-dependent manner, neurodevelopmental trajectories of the dopamine system across generations.

Maternal immune activation with high molecular weight poly(I:C) in Wistar rats leads to elevated immune cell chemoattractants

Maternal immune activation (MIA) with poly(I:C) is a preclinical paradigm for schizophrenia and autism research. Methodological variations, including poly(I:C) molecular weight, contribute to inconsistencies in behavioural and molecular outcomes. We established in Wistar rats that 4 mg/kg high molecular weight (HMW)-poly(I:C) on GD19 induces maternal sickness, smaller litters and maternal elevations of serum cytokines, including increases in monocyte chemoattractants. In adult offspring, we found that males have higher serum cytokines than females, and MIA did not alter peripheral cytokines in either sex. Our study will contribute to the effective use of the MIA model to elucidate the neurobiology of neurodevelopmental disorders.

Sources and Translational Relevance of Heterogeneity in Maternal Immune Activation Models.

The epidemiological literature reporting increased risk for neurodevelopmental and psychiatric disorders after prenatal exposure to maternal immune activation (MIA) is still evolving, and so are the attempts to model this association in animals. Epidemiological studies of MIA offer the advantage of directly evaluating human populations but are often limited in their ability to uncover pathogenic mechanisms. Animal models, on the other hand, are limited in their generalizability to psychiatric disorders but have made significant strides toward discovering causal relationships and biological pathways between MIA and neurobiological phenotypes. Like in any other model system, both planned and unplanned sources of variability exist in animal models of MIA. Therefore, the design, implementation, and interpretation of MIA models warrant a careful consideration of these sources, so that appropriate strategies can be developed to handle them satisfactorily. While every research group may have its own strategy to this aim, it is essential to report the methodological details of the chosen MIA model in order to enhancethe transparency and comparability of models across research laboratories. Even though it poses a challenge for attempts to compare experimental findings across laboratories, variability does not undermine the utility of MIA models for translational research. In fact, variability and heterogenous outcomes in MIA models offer unique opportunities for new discoveries and developments in this field, including the identification of disease pathways and molecular mechanisms determining susceptibility and resilience to MIA. This review summarizes the most important sources of variability in animal models of MIA and discusses how model variability can be used to investigate neurobiological and immunological factors causing phenotypic heterogeneity in offspring exposed to MIA.

Sex Differences in Psychosis: Focus on Animal Models.

Most psychiatric illnesses, such as schizophrenia, show profound sex differences in incidence, clinical presentation, course, and outcome. Fortunately, more recently the literature on sex differences and (to a lesser extent) effects of sex steroid hormones is expanding, and in this review we have focused on such studies in psychosis, both from a clinical/epidemiological and preclinical/animal model perspective. We begin by briefly describing the clinical evidence for sex differences in schizophrenia epidemiology, symptomatology, and pathophysiology. We then detail sex differences and sex hormone effects in behavioral animal models of psychosis, specifically psychotropic drug-induced locomotor hyperactivity and disruption of prepulse inhibition. We expand on the preclinical data to include developmental and genetic models of psychosis, such as the maternal immune activation model and neuregulin transgenic animals, respectively. Finally, we suggest several recommendations for future studies, in order to facilitate a better understanding of sex differences in the development of psychosis.

Maternal inflammation is hard for offspring to stomach

Individuals with neurodevelopmental disorders often experience comorbid gastrointestinal distress and dysregulated immune responses, yet the underlying mechanisms remain unclear. In this issue of Immunity, Kim etal. utilize a murine maternal immune activation model of autism and find that inflammation can alter the microbiota of mothers, which postnatally primes offspring CD4+ Tcells and increases susceptibility to intestinal inflammation.

Long-Term Effects of prophylactic MgSO4 in Maternal Immune Activation Rodent Model at Adolescence and Adulthood

MgSO4 has been used for the last two decades as a neuroprotective treatment in a variety of preterm conditions. Despite the putative advantages of MgSO4 as a neuroprotective agent in the preterm brain, the long-term molecular and behavioral function of MgSO4 as a neuroprotective agent has not been fully elucidated. The objectives of this study were to investigate the long-term effect of antenatal MgSO4, during late gestational, on offspring’s behavior in a mouse maternal immune activation (MIA) model in adolescence and adulthood, and to explore its influence on brain gene expression (e.g., ErbB signaling, pro-inflammatory and dopaminergic markers) in adulthood

P.0297 Selective downregulation of cortical mglu2 receptors in the maternal immune activation model of schizophrenia: association with histone posttranslational modifications

P.0297 Selective downregulation of cortical mglu2 receptors in the maternal immune activation model of schizophrenia: association with histone posttranslational modifications

P.0842 Weight and temperature monitoring of pregnant dams in the poly(I:C) maternal immune activation model of schizophrenia. Strain and batch influence

P.0842 Weight and temperature monitoring of pregnant dams in the poly(I:C) maternal immune activation model of schizophrenia. Strain and batch influence

Disruption of Alternative Splicing in the Amygdala of Pigs Exposed to Maternal Immune Activation

The inflammatory response of gestating females to infection or stress can disrupt gene expression in the offspring’s amygdala, resulting in lasting neurodevelopmental, physiological, and behavioral disorders. The effects of maternal immune activation (MIA) can be impacted by the offspring’s sex and exposure to additional stressors later in life. The objectives of this study were to investigate the disruption of alternative splicing patterns associated with MIA in the offspring’s amygdala and characterize this disruption in the context of the second stress of weaning and sex. Differential alternative splicing was tested on the RNA-seq profiles of a pig model of viral-induced MIA. Compared to controls, MIA was associated with the differential alternative splicing (FDR-adjusted p-value &lt; 0.1) of 292 and 240 genes in weaned females and males, respectively, whereas 132 and 176 genes were differentially spliced in control nursed female and male, respectively. The majority of the differentially spliced (FDR-adjusted p-value &lt; 0.001) genes (e.g., SHANK1, ZNF672, KCNA6) and many associated enriched pathways (e.g., Fc gamma R-mediated phagocytosis, non-alcoholic fatty liver disease, and cGMP-PKG signaling) have been reported in MIA-related disorders including autism and schizophrenia in humans. Differential alternative splicing associated with MIA was detected in the gene MAG across all sex-stress groups except for unstressed males and SLC2A11 across all groups except unstressed females. Precise understanding of the effect of MIA across second stressors and sexes necessitates the consideration of splicing isoform profiles.

The Role of Maternal Immune Activation in the Pathogenesis of Autism: A Review of the Evidence, Proposed Mechanisms and Implications for Treatment.

Autism spectrum disorder (ASD) is a neurodevelopmental disease that is characterized by a deficit in social interactions and communication, as well as repetitive and restrictive behaviors. Increasing lines of evidence suggest an important role for immune dysregulation and/or inflammation in the development of ASD. Recently, a relationship between inflammation, oxidative stress, and mitochondrial dysfunction has been reported in the brain tissue of individuals with ASD. Some recent studies have also reported oxidative stress and mitochondrial abnormalities in animal models of maternal immune activation (MIA). This review is focused on the hypothesis that MIA induces microglial activation, oxidative stress, and mitochondrial dysfunction, a deleterious trio in the brain that can lead to neuroinflammation and neurodevelopmental pathologies in offspring. Infection during pregnancy activates the mother’s immune system to release proinflammatory cytokines, such as IL-6, TNF-α, and others. Furthermore, these cytokines can directly cross the placenta and enter the fetal circulation, or activate resident immune cells, resulting in an increased production of proinflammatory cytokines, including IL-6. Proinflammatory cytokines that cross the blood–brain barrier (BBB) may initiate a neuroinflammation cascade, starting with the activation of the microglia. Inflammatory processes induce oxidative stress and mitochondrial dysfunction that, in turn, may exacerbate oxidative stress in a self-perpetuating vicious cycle that can lead to downstream abnormalities in brain development and behavior.